Loss of MYC Confers Resistance to Doxorubicin-induced Apoptosis by Preventing the Activation of Multiple Serine Protease- and Caspase-mediated Pathways

Grassilli, Emanuela; Ballabeni, Andrea; Maellaro, Emilia; Bello, Barbara Del; Helin, Kristian

doi:10.1074/jbc.m313532200

Cited by 36 publications

(38 citation statements)

References 39 publications

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“…Altogether, this indicates the involvement of caspase-independent apoptotic routes in mediating death in cardiac myocytes by DOX. This cannot be generalised because in other cell types (in our study and in previous reports) caspases seem to play a role in DOX-induced cell death (Nakamura et al, 2000;Grassilli et al, 2004;Kalivendi et al, 2005). Together this supports the idea that more than one mechanism can mediate programmed cell death, which depends on both the death stimulus provided and the cell type studied (Bröker et al, 2005).…”

Section: Discussionsupporting

confidence: 63%

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

et al. 2007

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Doxorubicin (DOX) is an antitumour agent for different types of cancer, but the dose-related cardiotoxicity limits its clinical use. To prevent this side effect we have developed the flavonoid monohydroxyethylrutoside (monoHER), a promising protective agent, which did not interfere with the antitumour activity of DOX. To obtain more insight in the mechanism underlying the selective protective effects of monoHER, we investigated whether monoHER (1 mM) affects DOX-induced apoptosis in neonatal rat cardiac myocytes (NeRCaMs), human endothelial cells (HUVECs) and the ovarian cancer cell lines A2780 and OVCAR-3. DOX-induced cell death was effectively reduced by monoHER in heart, endothelial and A2780 cells. OVCAR-3 cells were highly resistant to DOXinduced apoptosis. Experiments with the caspase-inhibitor zVAD-fmk showed that DOX-induced apoptosis was caspase-dependent in HUVECs and A2780 cells, whereas caspase-independent mechanisms seem to be important in NeRCaMs. MonoHER suppressed DOX-dependent activation of the mitochondrial apoptotic pathway in normal and A2780 cells as illustrated by p53 accumulation and activation of caspase-9 and -3 cleavage. Thus, monoHER acts by suppressing the activation of molecular mechanisms that mediate either caspase-dependent or -independent cell death. In light of the current work and our previous studies, the use of clinically achievable concentrations of monoHER has no influence on the antitumour activity of DOX whereas higher concentrations as used in the present study could influence the antitumour activity of DOX.

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Section: Discussionsupporting

confidence: 63%

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

et al. 2007

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“…Recent studies support a function for serine proteases in caspase-dependent or -independent apoptotic pathways. 35,36 Whether serine proteases are involved upstream or downstream of caspase activation, or alternatively act in parallel pathways in A3D8-induced apoptosis, remains to be determined. Although the nature of serine protease involved in A3D8-induced apoptosis of NB4 cells is still not characterized, we hypothesize that it is a trypsin-like protease since A3D8-induced apoptosis was inhibited by TLCK, a trypsin-like serine protease inhibitor, but not by TPCK, a chymotrypsin-like serine protease inhibitor.…”

Section: Cd44-induced Apoptosis In Aplmentioning

confidence: 99%

CD44 ligation induces apoptosis via caspase- and serine protease-dependent pathways in acute promyelocytic leukemia cells

et al. 2005

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We have recently reported that ligation of the CD44 cell surface antigen with A3D8 monoclonal antibody (mAb) triggers incomplete differentiation and apoptosis of the acute promyelocytic leukemia (APL)-derived NB4 cells. The present study characterizes the mechanisms underlying the apoptotic effect of A3D8 in NB4 cells. We show that A3D8 induces activation of both initiator caspase-8 and -9 and effector caspase-3 and -7 but only inhibition of caspase-3/7 and caspase-8 reduces A3D8-induced apoptosis. Moreover, A3D8 induces mitochondrial alterations (decrease in mitochondrial membrane potential DW m and cytochrome c release), which are reduced by caspase-8 inhibitor, suggesting that caspase-8 is primarily involved in A3D8-induced apoptosis of NB4 cells. However, the apoptotic process is independent of TNF-family death receptor signalling. Interestingly, the general serine protease inhibitor 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF) decreases A3D8-induced apoptosis and when combined with general caspase inhibitor displays an additive effect resulting in complete prevention of apoptosis. These results suggest that both caspase-dependent and serine protease-dependent pathways contribute to A3D8-induced apoptosis. Finally, A3D8 induces apoptosis in all-trans-retinoic acid-resistant NB4-derived cells and in APL primary blasts, characterizing the A3D8 anti-CD44 mAb as a novel class of apoptosis-inducing agent in APL.

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“…All cell lines were maintained in McCoy medium (Invitrogen) supplemented with 10% FBS (Invitrogen) and 1% penicillin-streptomycin at 37 C in 5% CO 2 . Cell lines stably interfered for each gene identified in the screen were obtained by retroviral infection and selection with the appropriate antibiotic as previously described (11). shRNAGSK3B target sequence GATGAGGTCTATCTTAATC (nt:1353-1371).…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

Inhibition of GSK3B Bypass Drug Resistance of p53-Null Colon Carcinomas by Enabling Necroptosis in Response to Chemotherapy

Grassilli

Narloch

Federzoni

et al. 2013

Clinical Cancer Research

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Purpose: Evasion from chemotherapy-induced apoptosis due to p53 loss strongly contributes to drug resistance. Identification of specific targets for the treatment of drug-resistant p53-null tumors would therefore increase the effectiveness of cancer therapy.Experimental Design: By using a kinase-directed short hairpin RNA library and HCT116p53KO drugresistant colon carcinoma cells, glycogen synthase kinase 3 beta (GSK3B) was identified as a target whose silencing bypasses drug resistance due to loss of p53. p53-null colon cancer cell lines with different sets of mutations were used to validate the role of GSK3B in sustaining resistance and to characterize cell death mechanisms triggered by chemotherapy when GSK3B is silenced. In vivo xenograft studies were conducted to confirm resensitization of drug-resistant cells to chemotherapy upon GSK3 inhibition. Colon cancer samples from a cohort of 50 chemotherapy-treated stage II patients were analyzed for active GSK3B expression.Results: Downregulation of GSK3B in various drug-resistant p53-null colon cancer cell lines abolished cell viability and colony growth after drug addition without affecting cell proliferation or cell cycle in untreated cells. Cell death of 5-fluorouracil (5FU)-treated p53-null GSK3B-silenced colon carcinoma cells occurred via PARP1-dependent and AIF-mediated but RIP1-independent necroptosis. In vivo studies showed that drug-resistant xenograft tumor mass was significantly reduced only when 5FU was given after GSK3B inhibition. Tissue microarray analysis of colon carcinoma samples from 5FU-treated patients revealed that GSK3B is significantly more activated in drug-resistant versus responsive patients.Conclusions: Targeting GSK3B, in combination with chemotherapy, may represent a novel strategy for the treatment of chemotherapy-resistant tumors.

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Loss of MYC Confers Resistance to Doxorubicin-induced Apoptosis by Preventing the Activation of Multiple Serine Protease- and Caspase-mediated Pathways

Cited by 36 publications

References 39 publications

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

CD44 ligation induces apoptosis via caspase- and serine protease-dependent pathways in acute promyelocytic leukemia cells

Inhibition of GSK3B Bypass Drug Resistance of p53-Null Colon Carcinomas by Enabling Necroptosis in Response to Chemotherapy

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